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Receptor-selective Agonists (receptor-selective + agonist)

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Medical Sciences	100%

Selected Abstracts

Tachykinin-induced contraction of the guinea-pig isolated oesophageal mucosa is mediated by NK2 receptors

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2000
Karen P Kerr
The tachykinin receptor present in the guinea-pig oesophageal mucosa that mediates contractile responses of the muscularis mucosae has been characterized, using functional in vitro experiments. The NK1 receptor-selective agonist, [Sar9(O2)Met11]SP and the NK3 receptor-selective agonists, [MePhe7]-NKB and senktide, produced no response at submicromolar concentrations. The NK2 receptor-selective agonists, [Nle10]-NKA(4,10), and GR 64,349 produced concentration-dependent contractile effects with pD2 values of 8.20±0.16 and 8.30±0.15, respectively. The concentration-response curve to the non-selective agonist, NKA (pD2=8.13±0.04) was shifted significantly rightwards only by the NK2 receptor-selective antagonist, GR 159,897 and was unaffected by the NK1 receptor-selective antagonist, SR 140,333 and the NK3 receptor-selective antagonist, SB 222,200. The NK2 receptor-selective antagonist, GR 159,897, exhibited an apparent competitive antagonism against the NK2 receptor-selective agonist, GR 64,349 (apparent pKB value=9.29±0.16) and against the non-selective agonist, NKA (apparent pKB value=8.71±0.19). The NK2 receptor-selective antagonist, SR 48,968 exhibited a non-competitive antagonism against the NK2 receptor-selective agonist, [Nle10]-NKA(4,10). The pKB value was 10.84±0.19. It is concluded that the guinea-pig isolated oesophageal mucosa is a useful preparation for studying the effects of NK2 receptor-selective agonists and antagonists as the contractile responses to various tachykinins are mediated solely by NK2 receptors. British Journal of Pharmacology (2000) 131, 1461,1467; doi:10.1038/sj.bjp.0703708 [source]

The potential for ,-opioid receptor agonists to be anti-emetic in humans: a review of clinical data

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2010
KEVIN D. JOHNSTON
In animal models of vomiting, ,-opioid (MOP, OP3) receptors mediate both emesis and anti-emesis. ,-receptors within the blood,brain barrier, mediating anti-emesis, are more rapidly accessible to lipid-soluble ,-opioid receptor agonists such as fentanyl than to morphine, and fentanyl has broad-spectrum anti-emetic effects in a number of species. Whether a similar situation exists in humans is not known. A search was performed for clinical studies comparing the emetic side effects of opioids administered peri-operatively in an attempt to identify differences between morphine and more lipid-soluble ,-receptor-selective agonists such as fentanyl. Overall, the evidence appears to suggest that fentanyl and other phenylpiperidines are associated with less nausea and vomiting than morphine, but not all studies support this, and fentanyl-like drugs are associated with nausea and vomiting per se. Good evidence, however, exists to show that fentanyl and alfentanil do not cause more nausea and vomiting than the ultra fast-acting remifentanil. Because remifentanil is cleared rapidly post-operatively, such trials suggest that the emetic side effects of fentanyl and alfentanil are minimal. The clinical evidence, although limited, is at least consistent with the possibility that central ,-opioid receptors may mediate anti-emesis in humans. It is possible that the role of ,-opioid agonists in anti-emesis may become clearer in the future as a result of the use of peripheral ,-opioid receptor antagonists. [source]

Constitutive activity of cannabinoid-2 (CB2) receptors plays an essential role in the protean agonism of (+)AM1241 and L768242

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009
I Mancini
Background and purpose:, Cannabinoid-2 (CB2) receptor-selective agonists have shown anti-nociceptive activity in models of neuropathic and inflammatory pain, and the two agonists most widely used, (+/,)AM1241 [(2-iodo-5-nitrophenyl)-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl-methanone] and L768242 [(2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone] (GW405833), have been suggested to be protean agonists. Here we investigated the role of the constitutive activity of CB2 receptors in (+)AM1241 and L768242 protean agonism. Experimental approach:, Pharmacological profiles of CB2 receptor ligands were evaluated in Chinese hamster ovary cells expressing recombinant human (hCB2) or rat (rCB2) receptors, by measuring modulation of cAMP. To assess the influence of constitutive activity on pharmacological profile, constitutive activity was abolished by pretreatment with AM630 [(6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl) methanone)], followed by extensive washing. Key results:, In cell lines expressing either hCB2 or rCB2 receptors, (+)AM1241 did not reverse forskolin stimulation of cAMP levels. Conversely, L768242 was an inverse agonist at both hCB2 and rCB2 receptors. Abolition of constitutive activity disclosed (+)AM1241 and L768242 agonist activity, while activity of CP55940 [5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxy-propyl)-cyclohexyl]-phenol] was unaffected and AM630 became a neutral antagonist. In presence of constitutively active CB2 receptors, (+)AM1241 antagonized CP55940, but when constitutive activity was abolished, it acted as a partial agonist with additive or antagonistic behaviour, depending on concentration. Conclusions and implications:, These results show that (+)AM1241 and L768242 are protean agonists at both hCB2 and rCB2 receptors. Abolition of constitutive activity reveals the agonist activity of these compounds. Thus, differences between in vivo and in vitro profiles of CB2 receptor agonists could be due to different levels of constitutive activity in recombinant versus native CB2 receptors. [source]